Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

Definitions

• nucleosides that have four non-hydrogen substituents in the 2' or 3 '-positions
• acylated forms of the nucleosides See for example, WO 01/90121 (USSN 09/864,078); WO 01/92282 (USSN 09/863,816); PCT/IB03/03901 (USSN 10/609,298); PCT/IB03/03246 (USSN
• the optionally protected branched nucleoside was then coupled with a suitable acyl donor, such as an acyl chloride and/or an acyl anhydride or an activated acid, in an appropriate protic or aprotic solvent and at a suitable reaction temperature, to provide the 2' or 3' prodrug of the branched nucleoside, optionally in the presence of a suitable coupling agent (see Synthetic Communications, 1978, 8(5): 327- 33; J Am. Chem. Soc, 1999, 121 (24): 5661-5; Bryant et al., Antimicrob. Agents
• a suitable acyl donor such as an acyl chloride and/or an acyl anhydride or an activated acid
• the nucleoside preferably was not protected, but was coupled directly to an alkanoic or amino acid residue via a carbodiimide-coupling reagent.
• a nucleoside with a protected organic acid in the presence of a coupling reagent (such as CDI), and a base (such as TEA), optionally in the presence of a base catalyst (such as DMAP), for example in a polar solvent (such as DMF and/or THF), results in the selective addition of the protected organic acid to the 3' -OH of the nucleoside, thereby forming a 3 '-prodrug of the nucleoside.
• a coupling reagent such as CDI
• a base such as TEA
• a base catalyst such as DMAP
• polar solvent such as DMF and/or THF
• a 2' or 3 '-branched nucleoside with a protected organic acid in the presence of a coupling reagent (such as CDI), base (such as TEA), optionally in the presence of a base catalyst (such as DMAP), and a polar solvent (such as THF and/or DMF) results in the addition of the protected organic acid selectively to the 3' -OH of the nucleoside, thereby forming a 3 '-prodrug of the nucleoside. Since the process occurs in only a single step, the time required for forming the prodrug product is significantly reduced from processes found in the prior art. In one embodiment of the present invention, the product yield is above 50%.
• the nucleoside with a free or reactive 3' -OH (or -SH) can be purchased or can be prepared by any published or unpublished means including standard reduction, oxidation, substitution and/or coupling techniques.
• the nucleoside is a 2' or 3 '-branched nucleoside.
• the nucleoside with a free 3' -OH (or -SH) is a 2'-deoxynucleoside such as 2'-deoxycytidine or 2'-deoxythymidine, which can be purchased or can be prepared by any published or unpublished means including standard reduction and coupling techniques.
• the 3 '-selectively acylated nucleoside can be prepared by reaction of the optionally protected organic acid with the nucleoside with a free 3'-OH (or -SH) in the presence of a coupling reagent and base(s).
• Suitable coupling reagents include EDC (1-
• the reagents can be added simultaneously or sequentially over a suitable period and temperature to allow the reaction to proceed at an acceptable rate without excessive side products.
• the optionally protected organic acid is stirred with the coupling reagent prior to addition of the nucleoside and/or base(s).
• the optionally protected organic acid such as an optionally protected amino acid, for example Boc-L-valine
• the coupling agent such as CDI. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
• some of the more volatile solvents e.g. THF
• base(s) e.g. TEA
• THF more volatile solvents
• base(s) e.g. TEA
• the 3 '-selectively esterified at the 3 '-position nucleoside can be reacted with a pharmaceutically acceptable inorganic or organic acid, such as HC1, in a solvent, such as a polar protic solvent, for example EtOH, to provide a pharmaceutically acceptable salt, such as a hydrochloride salt, as a final product.
• a pharmaceutically acceptable inorganic or organic acid such as HC1
• a solvent such as a polar protic solvent, for example EtOH
• the base is a purine base selected from the group consisting of N 6 -alkylpurines (including N-methyl purine), N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 - halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6- diaminopurine, and 6-chloropurine.
• N 6 -alkylpurines including N-methyl
• the base is a selected from the group consisting of:
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• the 2'-C- methyl branched nucleoside to be selectively esterified at the 3 '-position is
• protected refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent its further reaction or for other purposes.
• oxygen, nitrogen and phosphorus protecting groups are known to those skilled in the art of organic synthesis.
• alkaryl and alkylaryl refer to an alkyl group with an aryl substituent.
• aralkyl and arylalkyl refer to an aryl group with an alkyl substituent.
• non-natural amino acid refers to a carboxylic acid having an amino group terminus but that is not found in nature.
• the term is intended to embrace both D- and L-amino acids, and any tautomeric or stereoisomeric forms thereof.
• nucleoside base includes but is not limited to purine or pyrimidine bases.
• purine or pyrimidine base include, but are not limited to, adenine, N 6 -alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 - acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6- thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil
• the process of the present invention is not limited to the use of BOC as a protecting group.
• Other protecting groups such as, for example, substituted or unsubstituted silyl groups; substituted or unsubstituted ether groups like C-O-aralkyl, C-
• O-alkyl, or C-O-aryl O-alkyl, or C-O-aryl; aliphatic groups such as acyl or acetyl groups having an alkyl moiety that is straight-chained or branched; and any such groups that would not adversely affect the materials, reagents and conditions of the present invention as known to those of skill in the art and as taught by Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, 2 nd Edition (1991), may be used.
• Any organic solvents such as, for example, toluene may replace acetonitrile.
• Triethylamine and tetrahydrofuran were removed under reduced pressure at 43°C.
• the solution then was cooled to 10°C and neutralized with acetic acid to a pH of 7.7.
• the mixture was diluted with methylene chloride (100 mL) and brine (100 mL). This mixture was agitated for 10 minutes, the layers were split, and the aqueous layer was back extracted with 2 x 100 mL of methylene chloride.
• the organic layer was extracted with a solution of 10% malonic acid in water (4 x 100 mL).

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